The following are key points to remember from a European consensus statement on embolic strokes of undetermined source:

1. Embolic strokes of undetermined source (ESUS) are nonlacunar strokes where a convincing underlying stroke etiology (such as atrial fibrillation or internal carotid artery stenosis) is not identified after an appropriate diagnostic workup. The concept of ESUS was first introduced 10 years ago.
2. ESUS are common (occurring in one in six ischemic stroke patients), have a high risk of stroke recurrence (29% in 5 years), and represent an attractive target for novel or enhanced secondary stroke prevention strategies. The first intervention that was tested in the general ESUS population was stroke prevention with a direct oral anticoagulant (DOAC) compared to stroke prevention with aspirin monotherapy. In all three relevant trials, anticoagulation with a DOAC was not superior to aspirin monotherapy in prevention of recurrent stroke in ESUS patients. [Many in the stroke community were surprised and disappointed by these results.]
3. The authors of this position paper categorize the potential etiologies of ESUS into supracardiac (largely carotid) atherosclerosis, patent foramen ovale (PFO) and other right-to-left shunts, left atrial disease (including atrial arrhythmias and atrial cardiomyopathy), left ventricular (LV) disease, valvular heart disease, and cancer.
4. The degree of thromboembolic risk posed by carotid atherosclerosis may be informed by carotid plaque features rather than just the degree of carotid stenosis. These features include intraplaque hemorrhage, ulcerated plaque morphology, and intraluminal thrombus, among others. However, randomized controlled studies to guide best treatment (e.g., surgery vs. stenting vs. best medical management) of patients with high-risk nonstenotic carotid lesions are lacking.
5. PFO is common and found in approximately one-quarter of adults (twice as common as left-handedness). In ESUS patients <60 years old where no other potential stroke etiology is identified, percutaneous closure of PFO reduces the risk of subsequent ischemic stroke. Larger PFOs and PFOs associated with atrial septal aneurysm are considered highest risk.
6. Anticoagulation remains the standard of care for secondary stroke prevention in patients with atrial fibrillation, though the necessary “amount” of atrial fibrillation to implicate a need for anticoagulation remains a focus of study.
7. The ARCADIA trial (2024) randomized patients with ESUS and signs of atrial cardiopathy to apixaban versus aspirin. The trial was stopped for futility, as there was no difference in rates of stroke recurrence between patients in the apixaban group and patients in the aspirin group. [Many in the stroke community were surprised and disappointed by these results.]
8. Ischemic heart disease and dilated cardiomyopathy with reduced ejection fraction (EF) are the most common causes of LV dysfunction, which may cause stroke. [Based on the results of the WARCEF trial in 2012, some stroke providers treat ischemic stroke patients with LVEF <35% with anticoagulation to reduce the risk of recurrent stroke.]
9. In the year before cancer is diagnosed, there is a 59% increased risk of ischemic stroke, and 2-10% of patients with ischemic stroke are diagnosed with cancer in the subsequent year. About 50% of cancer-related strokes are classified as ESUS.
10. The potential causes of ESUS represent a heterogenous group of diseases, and multiple potential thromboembolic sources frequently coexist. The authors propose that a patient’s individual thromboembolic risk should be assessed by an accounting of the risk of all potential ESUS causes for that patient rather than the risk conferred by the most likely potential cause, and subsequently a bundle of secondary stroke prevention strategies should be pursued. [As ESUS secondary stroke prevention trials continue to disappoint the stroke community, I suspect the concept of ESUS will fall out of favor, and we will return to a “splitting” rather than a “lumping” approach to ESUS.]

Note: The text in square brackets denotes the Journal Scan author’s perspective.

Clinical Topics: Prevention, Vascular Medicine

Keywords: Embolic Stroke, Secondary Prevention

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